rs544247912

chr21-34792309-G-Achr21-34792309-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001754.5(RUNX1):c.1269C>T(p.Arg423=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000545 in 1,542,486 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. R423R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (2 hom.)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:7
• Conservation: PhyloP100: 0.642

Genes affected

RUNX1 (HGNC:10471): (RUNX family transcription factor 1) Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 21-34792309-G-A is Benign according to our data. Variant chr21-34792309-G-A is described in ClinVar as [Benign]. Clinvar id is 239042.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.642 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000559 (778/1391264) while in subpopulation MID AF= 0.00463 (26/5616). AF 95% confidence interval is 0.00324. There are 2 homozygotes in gnomad4_exome. There are 377 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck.
• BS2: High AC in GnomAd at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.1269C>T	p.Arg423=	synonymous_variant	9/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.1269C>T	p.Arg423=	synonymous_variant	9/9		NM_001754.5	A1

Frequencies

GnomAD3 genomes AF: 0.000410 AC: 62 AN: 151100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00896

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000340

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.000696 AC: 100 AN: 143620 Hom.: 0 AF XY: 0.000608 AC XY: 47 AN XY: 77364

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000325

Gnomad ASJ exome AF: 0.00698

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000875

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000559 AC: 778 AN: 1391264 Hom.: 2 Cov.: 37 AF XY: 0.000549 AC XY: 377 AN XY: 687008

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.000281

Gnomad4 ASJ exome AF: 0.00810

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000176

Gnomad4 FIN exome AF: 0.0000233

Gnomad4 NFE exome AF: 0.000439

Gnomad4 OTH exome AF: 0.000884

GnomAD4 genome AF: 0.000410 AC: 62 AN: 151222 Hom.: 0 Cov.: 32 AF XY: 0.000325 AC XY: 24 AN XY: 73906

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00896

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.000340

Gnomad4 OTH AF: 0.000477

Alfa AF: 0.000964 Hom.: 0

Bravo AF: 0.000419

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Aug 02, 2019	The MAF for the synonymous variant, NM_001754.4:c.1269C>T (p.Arg423=) is 0.00275 (0.2%, 14/5096 alleles) in the non-Finnish European subpopulation of the ExAC cohort, which is >/= 0.0015 (0.15%) (BA1). This variant is predicted by SSF and MES to lead to an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% AND no putative cryptic splice sites are created (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP4. -

Acute myeloid leukemia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 17, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 13, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2017

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Jul 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.1
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs544247912; hg19: chr21-36164606;